Federal Practitioner

Uptake of the approved extended-interval dosing regimen for pembrolizumab has been poor, according to a review of Veterans Health Administration data.

In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.

The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.

Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.

However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.

Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.

Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.

Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.

And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.

The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.

Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.

“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.

“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.

In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.

It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.

If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.

“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.

To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”

Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.

Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”

Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.

The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.

A version of this article first appeared on Medscape.com.

Uptake of the approved extended-interval dosing regimen for pembrolizumab has been poor, according to a review of Veterans Health Administration data.

In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.

The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.

Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.

However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.

Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.

Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.

Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.

And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.

The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.

Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.

“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.

“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.

In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.

It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.

If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.

“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.

To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”

Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.

Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”

Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.

The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.

A version of this article first appeared on Medscape.com.

Uptake of the approved extended-interval dosing regimen for pembrolizumab has been poor, according to a review of Veterans Health Administration data.

In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.

The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.

Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.

However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.

Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.

Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.

Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.

And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.

The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.

Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.

“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.

“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.

In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.

It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.

If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.

“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.

To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”

Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.

Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”

Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.

The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.

A version of this article first appeared on Medscape.com.

LONDON – A little over a decade ago, Four Seasons Health Care was among the largest long-term care home companies in Britain, operating 500 sites with 20,000 residents and more than 60 specialist centers. Domestic and global private equity investors had supercharged the company’s growth, betting that the rising needs of aging Britons would yield big returns.

Within weeks, the Four Seasons brand may be finished.

Christie & Co., a commercial real estate broker, splashed a summer sale across its website that signaled the demise: The last 111 Four Seasons facilities in England, Scotland, and Jersey were on the market. Already sold were its 29 homes in Northern Ireland.

Four Seasons collapsed after years of private equity investors rolling in one after another to buy its business, sell its real estate, and at times wrest multimillion-dollar profits through complex debt schemes – until the last big equity fund, Terra Firma, which in 2012 paid about $1.3 billion for the company, was caught short.

In a country where government health care is a right, the Four Seasons story exemplifies the high-stakes rise – and, ultimately, fall – of private equity investment in health and social services. Hanging over society’s most vulnerable patients, these heavily leveraged deals failed to account for the cost of their care. Private equity firms are known for making a profit on quick-turnaround investments.

“People often say: ‘Why have American investors, as well as professional investors here and in other countries, poured so much into this sector?’ I think they were dazzled by the potential of the demographics,” said Nick Hood, an analyst at Opus Restructuring & Insolvency in London, which advises care homes – the British equivalent of U.S. nursing homes or assisted living facilities. They “saw the baby boomers aging and thought there would be infinite demands.”

What they missed, Mr. Hood said, “was that about half of all the residents in U.K. homes are funded by the government in one way or another. They aren’t private pay – and they’ve got no money.”
 

Residents as ‘revenue streams’

As in the United States, long-term care homes in Britain serve a mixed market of public- and private-pay residents, and those whose balance sheets rest heavily on government payments are stressed even in better economic times. Andrew Dobbie, a community officer for Unison, a union that represents care home workers, said private equity investors often see homes like Four Seasons as having “two revenue streams, the properties themselves and the residents,” with efficiencies to exploit.

But investors don’t always understand what caregivers do, he said, or that older residents require more time than spreadsheets have calculated. “That’s a problem when you are looking at operating care homes,” Mr. Dobbie said. “Care workers need to have soft skills to work with a vulnerable group of people. It’s not the same skills as stocking shelves in a supermarket.”

A recent study, funded in part by Unison and conducted by University of Surrey researchers, found big changes in the quality of care after private equity investments. More than a dozen staff members, who weren’t identified by name or facility, said companies were “cutting corners” to curb costs because their priority was profit. Staffers said “these changes meant residents sometimes went without the appropriate care, timely medication or sufficient sanitary supplies.”

In August, the House of Commons received a sobering account: The number of adults 65 and older who will need care is speedily rising, estimated to go from 3.5 million in 2018 to 5.2 million in 2038. Yet workers at care homes are among the lowest paid in health care.

“The covid-19 pandemic shone a light on the adult social care sector,” according to the parliamentary report, which noted that “many frustrated and burnt out care workers left” for better-paying jobs. The report’s advice in a year of soaring inflation and energy costs? The government should add “at least £7 billion a year” – more than $8 billion – or risk deterioration of care.

Britain’s care homes are separate from the much-lauded National Health Service, funded by the government. Care homes rely on support from local authorities, akin to counties in the United States. But they have seen a sharp drop in funding from the British government, which cut a third of its payments in the past decade. When the pandemic hit, the differences were apparent: Care home workers were not afforded masks, gloves, or gowns to shield them from the deadly virus.

Years ago, care homes were largely run by families or local entities. In the 1990s, the government promoted privatization, triggering investments and consolidations. Today, private equity firms own three of the country’s five biggest care home providers.

Chris Thomas, a research fellow at the Institute for Public Policy Research, said investors benefited from scant financial oversight. “The accounting practices are horrendously complicated and meant to be complicated,” he said. Local authorities try “to regulate more, but they don’t have the expertise.”
 

The financial shuffle

At Four Seasons, the speed of change was dizzying. From 2004 to 2017, big money came and went, with revenue at times threaded through multiple offshore vehicles. Among the groups that owned Four Seasons, in part or in its entirety: British private equity firm Alchemy Partners; Allianz Capital Partners, a German private equity firm; Three Delta, an investment fund backed by Qatar; the American hedge fund Monarch Alternative Capital; and Terra Firma, the British private equity group that wallowed in debt demands. H/2 Capital Partners, a hedge fund in Connecticut, was Four Seasons’ main creditor and took over. By 2019, Four Seasons was managed by insolvency experts.

Pressed on whether Four Seasons would exist in any form after the current sale of its property and businesses, MHP Communications, representing the company, said in an email: “It is too early in the process to speculate about the future of the brand.”

Vivek Kotecha, an accountant who has examined the Four Seasons financial shuffle and coauthored the Unison report, said private equity investment – in homes for older residents and, increasingly, in facilities for troubled children – is now part of the financial mainstream. The consulting firm McKinsey in 2022estimated that private markets manage nearly $10 trillion in assets, making them a dominant force in global markets.

“What you find in America with private equity is much the same here,” said Mr. Kotecha, the founder of Trinava Consulting in London. “They are often the same firms, doing the same things.” What was remarkable about Four Seasons was the enormous liability from high-yield bonds that underpinned the deal – one equaling $514 million at 8.75% interest and another for $277 million at 12.75% interest.

Guy Hands, the high-flying British founder of Terra Firma, bought Four Seasons in 2012, soon after losing an epic court battle with Citigroup over the purchase price of the music company EMI Group. Terra Firma acquired the care homes and then a gardening business with more than 100 stores. Neither proved easy, or good, bets. Hands, a Londoner who moved offshore to Guernsey, declined through a representative to discuss Four Seasons.

Mr. Kotecha, however, helped the BBC try to make sense of Four Seasons’ holdings by tracking financial filings. It was “the most complicated spreadsheet I’ve ever seen,” Mr. Kotecha said. “I think there were more subsidiaries involved in Four Seasons’ care homes than there were with General Motors in Europe.”

As Britain’s small homes were swept up in consolidations, some financial practices were dubious. At times, businesses sold the buildings as lease-back deals – not a problem at first – that, after multiple purchases, left operators paying rent with heavy interest that sapped operating budgets. By 2020, some care homes were estimated to be spending as much as 16% of their bed fees on debt payments, according to parliamentary testimony this year.

How could that happen? In part, for-profit providers – backed by private-equity groups and other corporations – had subsidiaries of their parent companies act as lender, setting the rates.

Britain’s elder care was unrecognizable within a generation. By 2022, private-equity companies alone accounted for 55,000 beds, or about 12.6% of the total for-profit care beds for older people in the United Kingdom, according to LaingBuisson, a health care consultancy. LaingBuisson calculated that the average residential care home fee as of February 2022 was about $44,700 a year; the average nursing home fee was $62,275 a year.

From 1980 to 2018, the number of residential care beds provided by local authorities fell 88% – from 141,719 to 17,100, according to the nonprofit Centre for Health and the Public Interest. Independent operators – nonprofits and for-profits – moved in, it said, controlling 243,000 beds by 2018. Nursing homes saw a similar shift: Private providers accounted for 194,100 beds in 2018, compared with 25,500 decades earlier.
 

Beyond government control

British lawmakers in the winter of 2021-2022 tried – and failed – to bolster financial reporting rules for care homes, including banning the use of government funds to pay off debt.

“I don’t have a problem with offshore companies that make profits if they offer good services. I don’t have a problem with private equity and hedge funds who deliver good returns to their shareholders,” Ros Altmann, a Conservative Party member in the House of Lords and a pension expert, said in a February debate. “I do have a problem if those companies are taking advantage of some of the most vulnerable people in our society without oversight, without controls.”

She cited Four Seasons as an example of how regulators “have no control over the financial models that are used.” Ms. Altmann warned that economic headwinds could worsen matters: “We now have very heavily debt-laden [homes] in an environment where interest rates are heading upward.”

In August, the Bank of England raised borrowing rates. It now forecasts double-digit inflation – as much as 11% – through 2023.

And that leaves care home owner Robert Kilgour pensive about whether government grasps the risks and possibilities that the sector is facing. “It’s a struggle, and it’s becoming more of a struggle,” he said. A global energy crisis is the latest unexpected emergency. Mr. Kilgour said he recently signed electricity contracts, for April 2023, at rates that will rise by 200%. That means an extra $2,400 a day in utility costs for his homes.

Mr. Kilgour founded Four Seasons, opening its first home, in Fife, Scotland, in 1989. His ambition for its growth was modest: “Ten by 2000.” That changed in 1999 when Alchemy swooped in to expand nationally. Mr. Kilgour had left Four Seasons by 2004, turning to other ventures.

Still, he saw opportunity in elder care and opened Renaissance Care, which now operates 16 homes with 750 beds in Scotland. “I missed it,” he said in an interview in London. “It’s people and it’s property, and I like that.”

“People asked me if I had any regrets about selling to private equity. Well, no, the people I dealt with were very fair, very straight. There were no shenanigans,” Mr. Kilgour said, noting that Alchemy made money but invested as well.

Mr. Kilgour said the pandemic motivated him to improve his business. He is spending millions on new LED lighting and boilers, as well as training staffers on digital record-keeping, all to winnow costs. He increased hourly wages by 5%, but employees have suggested other ways to retain staff: shorter shifts and workdays that fit school schedules or allow them to care for their own older relatives.

Debates over whether the government should move back into elder care make little sense to Mr. Kilgour. Britain has had private care for decades, and he doesn’t see that changing. Instead, operators need help balancing private and publicly funded beds “so you have a blended rate for care and some certainty in the business.”

Consolidations are slowing, he said, which might be part of a long-overdue reckoning. “The idea of 200, 300, 400 care homes – that big is good and big is best – those days are gone,” Mr. Kilgour said.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

LONDON – A little over a decade ago, Four Seasons Health Care was among the largest long-term care home companies in Britain, operating 500 sites with 20,000 residents and more than 60 specialist centers. Domestic and global private equity investors had supercharged the company’s growth, betting that the rising needs of aging Britons would yield big returns.

Within weeks, the Four Seasons brand may be finished.

Christie & Co., a commercial real estate broker, splashed a summer sale across its website that signaled the demise: The last 111 Four Seasons facilities in England, Scotland, and Jersey were on the market. Already sold were its 29 homes in Northern Ireland.

Four Seasons collapsed after years of private equity investors rolling in one after another to buy its business, sell its real estate, and at times wrest multimillion-dollar profits through complex debt schemes – until the last big equity fund, Terra Firma, which in 2012 paid about $1.3 billion for the company, was caught short.

In a country where government health care is a right, the Four Seasons story exemplifies the high-stakes rise – and, ultimately, fall – of private equity investment in health and social services. Hanging over society’s most vulnerable patients, these heavily leveraged deals failed to account for the cost of their care. Private equity firms are known for making a profit on quick-turnaround investments.

“People often say: ‘Why have American investors, as well as professional investors here and in other countries, poured so much into this sector?’ I think they were dazzled by the potential of the demographics,” said Nick Hood, an analyst at Opus Restructuring & Insolvency in London, which advises care homes – the British equivalent of U.S. nursing homes or assisted living facilities. They “saw the baby boomers aging and thought there would be infinite demands.”

What they missed, Mr. Hood said, “was that about half of all the residents in U.K. homes are funded by the government in one way or another. They aren’t private pay – and they’ve got no money.”
 

Residents as ‘revenue streams’

As in the United States, long-term care homes in Britain serve a mixed market of public- and private-pay residents, and those whose balance sheets rest heavily on government payments are stressed even in better economic times. Andrew Dobbie, a community officer for Unison, a union that represents care home workers, said private equity investors often see homes like Four Seasons as having “two revenue streams, the properties themselves and the residents,” with efficiencies to exploit.

But investors don’t always understand what caregivers do, he said, or that older residents require more time than spreadsheets have calculated. “That’s a problem when you are looking at operating care homes,” Mr. Dobbie said. “Care workers need to have soft skills to work with a vulnerable group of people. It’s not the same skills as stocking shelves in a supermarket.”

A recent study, funded in part by Unison and conducted by University of Surrey researchers, found big changes in the quality of care after private equity investments. More than a dozen staff members, who weren’t identified by name or facility, said companies were “cutting corners” to curb costs because their priority was profit. Staffers said “these changes meant residents sometimes went without the appropriate care, timely medication or sufficient sanitary supplies.”

In August, the House of Commons received a sobering account: The number of adults 65 and older who will need care is speedily rising, estimated to go from 3.5 million in 2018 to 5.2 million in 2038. Yet workers at care homes are among the lowest paid in health care.

“The covid-19 pandemic shone a light on the adult social care sector,” according to the parliamentary report, which noted that “many frustrated and burnt out care workers left” for better-paying jobs. The report’s advice in a year of soaring inflation and energy costs? The government should add “at least £7 billion a year” – more than $8 billion – or risk deterioration of care.

Britain’s care homes are separate from the much-lauded National Health Service, funded by the government. Care homes rely on support from local authorities, akin to counties in the United States. But they have seen a sharp drop in funding from the British government, which cut a third of its payments in the past decade. When the pandemic hit, the differences were apparent: Care home workers were not afforded masks, gloves, or gowns to shield them from the deadly virus.

Years ago, care homes were largely run by families or local entities. In the 1990s, the government promoted privatization, triggering investments and consolidations. Today, private equity firms own three of the country’s five biggest care home providers.

Chris Thomas, a research fellow at the Institute for Public Policy Research, said investors benefited from scant financial oversight. “The accounting practices are horrendously complicated and meant to be complicated,” he said. Local authorities try “to regulate more, but they don’t have the expertise.”
 

The financial shuffle

At Four Seasons, the speed of change was dizzying. From 2004 to 2017, big money came and went, with revenue at times threaded through multiple offshore vehicles. Among the groups that owned Four Seasons, in part or in its entirety: British private equity firm Alchemy Partners; Allianz Capital Partners, a German private equity firm; Three Delta, an investment fund backed by Qatar; the American hedge fund Monarch Alternative Capital; and Terra Firma, the British private equity group that wallowed in debt demands. H/2 Capital Partners, a hedge fund in Connecticut, was Four Seasons’ main creditor and took over. By 2019, Four Seasons was managed by insolvency experts.

Pressed on whether Four Seasons would exist in any form after the current sale of its property and businesses, MHP Communications, representing the company, said in an email: “It is too early in the process to speculate about the future of the brand.”

Vivek Kotecha, an accountant who has examined the Four Seasons financial shuffle and coauthored the Unison report, said private equity investment – in homes for older residents and, increasingly, in facilities for troubled children – is now part of the financial mainstream. The consulting firm McKinsey in 2022estimated that private markets manage nearly $10 trillion in assets, making them a dominant force in global markets.

“What you find in America with private equity is much the same here,” said Mr. Kotecha, the founder of Trinava Consulting in London. “They are often the same firms, doing the same things.” What was remarkable about Four Seasons was the enormous liability from high-yield bonds that underpinned the deal – one equaling $514 million at 8.75% interest and another for $277 million at 12.75% interest.

Guy Hands, the high-flying British founder of Terra Firma, bought Four Seasons in 2012, soon after losing an epic court battle with Citigroup over the purchase price of the music company EMI Group. Terra Firma acquired the care homes and then a gardening business with more than 100 stores. Neither proved easy, or good, bets. Hands, a Londoner who moved offshore to Guernsey, declined through a representative to discuss Four Seasons.

Mr. Kotecha, however, helped the BBC try to make sense of Four Seasons’ holdings by tracking financial filings. It was “the most complicated spreadsheet I’ve ever seen,” Mr. Kotecha said. “I think there were more subsidiaries involved in Four Seasons’ care homes than there were with General Motors in Europe.”

As Britain’s small homes were swept up in consolidations, some financial practices were dubious. At times, businesses sold the buildings as lease-back deals – not a problem at first – that, after multiple purchases, left operators paying rent with heavy interest that sapped operating budgets. By 2020, some care homes were estimated to be spending as much as 16% of their bed fees on debt payments, according to parliamentary testimony this year.

How could that happen? In part, for-profit providers – backed by private-equity groups and other corporations – had subsidiaries of their parent companies act as lender, setting the rates.

Britain’s elder care was unrecognizable within a generation. By 2022, private-equity companies alone accounted for 55,000 beds, or about 12.6% of the total for-profit care beds for older people in the United Kingdom, according to LaingBuisson, a health care consultancy. LaingBuisson calculated that the average residential care home fee as of February 2022 was about $44,700 a year; the average nursing home fee was $62,275 a year.

From 1980 to 2018, the number of residential care beds provided by local authorities fell 88% – from 141,719 to 17,100, according to the nonprofit Centre for Health and the Public Interest. Independent operators – nonprofits and for-profits – moved in, it said, controlling 243,000 beds by 2018. Nursing homes saw a similar shift: Private providers accounted for 194,100 beds in 2018, compared with 25,500 decades earlier.
 

Beyond government control

British lawmakers in the winter of 2021-2022 tried – and failed – to bolster financial reporting rules for care homes, including banning the use of government funds to pay off debt.

“I don’t have a problem with offshore companies that make profits if they offer good services. I don’t have a problem with private equity and hedge funds who deliver good returns to their shareholders,” Ros Altmann, a Conservative Party member in the House of Lords and a pension expert, said in a February debate. “I do have a problem if those companies are taking advantage of some of the most vulnerable people in our society without oversight, without controls.”

She cited Four Seasons as an example of how regulators “have no control over the financial models that are used.” Ms. Altmann warned that economic headwinds could worsen matters: “We now have very heavily debt-laden [homes] in an environment where interest rates are heading upward.”

In August, the Bank of England raised borrowing rates. It now forecasts double-digit inflation – as much as 11% – through 2023.

And that leaves care home owner Robert Kilgour pensive about whether government grasps the risks and possibilities that the sector is facing. “It’s a struggle, and it’s becoming more of a struggle,” he said. A global energy crisis is the latest unexpected emergency. Mr. Kilgour said he recently signed electricity contracts, for April 2023, at rates that will rise by 200%. That means an extra $2,400 a day in utility costs for his homes.

Mr. Kilgour founded Four Seasons, opening its first home, in Fife, Scotland, in 1989. His ambition for its growth was modest: “Ten by 2000.” That changed in 1999 when Alchemy swooped in to expand nationally. Mr. Kilgour had left Four Seasons by 2004, turning to other ventures.

Still, he saw opportunity in elder care and opened Renaissance Care, which now operates 16 homes with 750 beds in Scotland. “I missed it,” he said in an interview in London. “It’s people and it’s property, and I like that.”

“People asked me if I had any regrets about selling to private equity. Well, no, the people I dealt with were very fair, very straight. There were no shenanigans,” Mr. Kilgour said, noting that Alchemy made money but invested as well.

Mr. Kilgour said the pandemic motivated him to improve his business. He is spending millions on new LED lighting and boilers, as well as training staffers on digital record-keeping, all to winnow costs. He increased hourly wages by 5%, but employees have suggested other ways to retain staff: shorter shifts and workdays that fit school schedules or allow them to care for their own older relatives.

Debates over whether the government should move back into elder care make little sense to Mr. Kilgour. Britain has had private care for decades, and he doesn’t see that changing. Instead, operators need help balancing private and publicly funded beds “so you have a blended rate for care and some certainty in the business.”

Consolidations are slowing, he said, which might be part of a long-overdue reckoning. “The idea of 200, 300, 400 care homes – that big is good and big is best – those days are gone,” Mr. Kilgour said.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

LONDON – A little over a decade ago, Four Seasons Health Care was among the largest long-term care home companies in Britain, operating 500 sites with 20,000 residents and more than 60 specialist centers. Domestic and global private equity investors had supercharged the company’s growth, betting that the rising needs of aging Britons would yield big returns.

Within weeks, the Four Seasons brand may be finished.

Christie & Co., a commercial real estate broker, splashed a summer sale across its website that signaled the demise: The last 111 Four Seasons facilities in England, Scotland, and Jersey were on the market. Already sold were its 29 homes in Northern Ireland.

Four Seasons collapsed after years of private equity investors rolling in one after another to buy its business, sell its real estate, and at times wrest multimillion-dollar profits through complex debt schemes – until the last big equity fund, Terra Firma, which in 2012 paid about $1.3 billion for the company, was caught short.

In a country where government health care is a right, the Four Seasons story exemplifies the high-stakes rise – and, ultimately, fall – of private equity investment in health and social services. Hanging over society’s most vulnerable patients, these heavily leveraged deals failed to account for the cost of their care. Private equity firms are known for making a profit on quick-turnaround investments.

“People often say: ‘Why have American investors, as well as professional investors here and in other countries, poured so much into this sector?’ I think they were dazzled by the potential of the demographics,” said Nick Hood, an analyst at Opus Restructuring & Insolvency in London, which advises care homes – the British equivalent of U.S. nursing homes or assisted living facilities. They “saw the baby boomers aging and thought there would be infinite demands.”

What they missed, Mr. Hood said, “was that about half of all the residents in U.K. homes are funded by the government in one way or another. They aren’t private pay – and they’ve got no money.”
 

Residents as ‘revenue streams’

As in the United States, long-term care homes in Britain serve a mixed market of public- and private-pay residents, and those whose balance sheets rest heavily on government payments are stressed even in better economic times. Andrew Dobbie, a community officer for Unison, a union that represents care home workers, said private equity investors often see homes like Four Seasons as having “two revenue streams, the properties themselves and the residents,” with efficiencies to exploit.

But investors don’t always understand what caregivers do, he said, or that older residents require more time than spreadsheets have calculated. “That’s a problem when you are looking at operating care homes,” Mr. Dobbie said. “Care workers need to have soft skills to work with a vulnerable group of people. It’s not the same skills as stocking shelves in a supermarket.”

A recent study, funded in part by Unison and conducted by University of Surrey researchers, found big changes in the quality of care after private equity investments. More than a dozen staff members, who weren’t identified by name or facility, said companies were “cutting corners” to curb costs because their priority was profit. Staffers said “these changes meant residents sometimes went without the appropriate care, timely medication or sufficient sanitary supplies.”

In August, the House of Commons received a sobering account: The number of adults 65 and older who will need care is speedily rising, estimated to go from 3.5 million in 2018 to 5.2 million in 2038. Yet workers at care homes are among the lowest paid in health care.

“The covid-19 pandemic shone a light on the adult social care sector,” according to the parliamentary report, which noted that “many frustrated and burnt out care workers left” for better-paying jobs. The report’s advice in a year of soaring inflation and energy costs? The government should add “at least £7 billion a year” – more than $8 billion – or risk deterioration of care.

Britain’s care homes are separate from the much-lauded National Health Service, funded by the government. Care homes rely on support from local authorities, akin to counties in the United States. But they have seen a sharp drop in funding from the British government, which cut a third of its payments in the past decade. When the pandemic hit, the differences were apparent: Care home workers were not afforded masks, gloves, or gowns to shield them from the deadly virus.

Years ago, care homes were largely run by families or local entities. In the 1990s, the government promoted privatization, triggering investments and consolidations. Today, private equity firms own three of the country’s five biggest care home providers.

Chris Thomas, a research fellow at the Institute for Public Policy Research, said investors benefited from scant financial oversight. “The accounting practices are horrendously complicated and meant to be complicated,” he said. Local authorities try “to regulate more, but they don’t have the expertise.”
 

The financial shuffle

At Four Seasons, the speed of change was dizzying. From 2004 to 2017, big money came and went, with revenue at times threaded through multiple offshore vehicles. Among the groups that owned Four Seasons, in part or in its entirety: British private equity firm Alchemy Partners; Allianz Capital Partners, a German private equity firm; Three Delta, an investment fund backed by Qatar; the American hedge fund Monarch Alternative Capital; and Terra Firma, the British private equity group that wallowed in debt demands. H/2 Capital Partners, a hedge fund in Connecticut, was Four Seasons’ main creditor and took over. By 2019, Four Seasons was managed by insolvency experts.

Pressed on whether Four Seasons would exist in any form after the current sale of its property and businesses, MHP Communications, representing the company, said in an email: “It is too early in the process to speculate about the future of the brand.”

Vivek Kotecha, an accountant who has examined the Four Seasons financial shuffle and coauthored the Unison report, said private equity investment – in homes for older residents and, increasingly, in facilities for troubled children – is now part of the financial mainstream. The consulting firm McKinsey in 2022estimated that private markets manage nearly $10 trillion in assets, making them a dominant force in global markets.

“What you find in America with private equity is much the same here,” said Mr. Kotecha, the founder of Trinava Consulting in London. “They are often the same firms, doing the same things.” What was remarkable about Four Seasons was the enormous liability from high-yield bonds that underpinned the deal – one equaling $514 million at 8.75% interest and another for $277 million at 12.75% interest.

Guy Hands, the high-flying British founder of Terra Firma, bought Four Seasons in 2012, soon after losing an epic court battle with Citigroup over the purchase price of the music company EMI Group. Terra Firma acquired the care homes and then a gardening business with more than 100 stores. Neither proved easy, or good, bets. Hands, a Londoner who moved offshore to Guernsey, declined through a representative to discuss Four Seasons.

Mr. Kotecha, however, helped the BBC try to make sense of Four Seasons’ holdings by tracking financial filings. It was “the most complicated spreadsheet I’ve ever seen,” Mr. Kotecha said. “I think there were more subsidiaries involved in Four Seasons’ care homes than there were with General Motors in Europe.”

As Britain’s small homes were swept up in consolidations, some financial practices were dubious. At times, businesses sold the buildings as lease-back deals – not a problem at first – that, after multiple purchases, left operators paying rent with heavy interest that sapped operating budgets. By 2020, some care homes were estimated to be spending as much as 16% of their bed fees on debt payments, according to parliamentary testimony this year.

How could that happen? In part, for-profit providers – backed by private-equity groups and other corporations – had subsidiaries of their parent companies act as lender, setting the rates.

Britain’s elder care was unrecognizable within a generation. By 2022, private-equity companies alone accounted for 55,000 beds, or about 12.6% of the total for-profit care beds for older people in the United Kingdom, according to LaingBuisson, a health care consultancy. LaingBuisson calculated that the average residential care home fee as of February 2022 was about $44,700 a year; the average nursing home fee was $62,275 a year.

From 1980 to 2018, the number of residential care beds provided by local authorities fell 88% – from 141,719 to 17,100, according to the nonprofit Centre for Health and the Public Interest. Independent operators – nonprofits and for-profits – moved in, it said, controlling 243,000 beds by 2018. Nursing homes saw a similar shift: Private providers accounted for 194,100 beds in 2018, compared with 25,500 decades earlier.
 

Beyond government control

British lawmakers in the winter of 2021-2022 tried – and failed – to bolster financial reporting rules for care homes, including banning the use of government funds to pay off debt.

“I don’t have a problem with offshore companies that make profits if they offer good services. I don’t have a problem with private equity and hedge funds who deliver good returns to their shareholders,” Ros Altmann, a Conservative Party member in the House of Lords and a pension expert, said in a February debate. “I do have a problem if those companies are taking advantage of some of the most vulnerable people in our society without oversight, without controls.”

She cited Four Seasons as an example of how regulators “have no control over the financial models that are used.” Ms. Altmann warned that economic headwinds could worsen matters: “We now have very heavily debt-laden [homes] in an environment where interest rates are heading upward.”

In August, the Bank of England raised borrowing rates. It now forecasts double-digit inflation – as much as 11% – through 2023.

And that leaves care home owner Robert Kilgour pensive about whether government grasps the risks and possibilities that the sector is facing. “It’s a struggle, and it’s becoming more of a struggle,” he said. A global energy crisis is the latest unexpected emergency. Mr. Kilgour said he recently signed electricity contracts, for April 2023, at rates that will rise by 200%. That means an extra $2,400 a day in utility costs for his homes.

Mr. Kilgour founded Four Seasons, opening its first home, in Fife, Scotland, in 1989. His ambition for its growth was modest: “Ten by 2000.” That changed in 1999 when Alchemy swooped in to expand nationally. Mr. Kilgour had left Four Seasons by 2004, turning to other ventures.

Still, he saw opportunity in elder care and opened Renaissance Care, which now operates 16 homes with 750 beds in Scotland. “I missed it,” he said in an interview in London. “It’s people and it’s property, and I like that.”

“People asked me if I had any regrets about selling to private equity. Well, no, the people I dealt with were very fair, very straight. There were no shenanigans,” Mr. Kilgour said, noting that Alchemy made money but invested as well.

Mr. Kilgour said the pandemic motivated him to improve his business. He is spending millions on new LED lighting and boilers, as well as training staffers on digital record-keeping, all to winnow costs. He increased hourly wages by 5%, but employees have suggested other ways to retain staff: shorter shifts and workdays that fit school schedules or allow them to care for their own older relatives.

Debates over whether the government should move back into elder care make little sense to Mr. Kilgour. Britain has had private care for decades, and he doesn’t see that changing. Instead, operators need help balancing private and publicly funded beds “so you have a blended rate for care and some certainty in the business.”

Consolidations are slowing, he said, which might be part of a long-overdue reckoning. “The idea of 200, 300, 400 care homes – that big is good and big is best – those days are gone,” Mr. Kilgour said.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Spironolactone, a potassium-sparing diuretic typically used to treat heart failure and hypertension, shows promise in treating alcohol use disorder (AUD), new research suggests.

Researchers at the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and Yale University, New Haven, Conn., investigated the impact of spironolactone on AUD.

Initially, they studied rodents and found that spironolactone reduced binge drinking in mice and reduced self-administration of alcohol in rats without adversely affecting food or water intake or causing motor or coordination problems.

They also analyzed electronic health records of patients drawn from the United States Veterans Affairs health care system to explore potential changes in alcohol use after spironolactone treatment was initiated for other conditions and found a significant link between spironolactone treatment and reduction in self-reported alcohol consumption, with the largest effects observed among those who reported hazardous/heavy episodic alcohol use prior to starting spironolactone treatment.

“Combining findings across three species and different types of research studies, and then seeing similarities in these data, gives us confidence that we are onto something potentially important scientifically and clinically,” senior coauthor Lorenzo Leggio, MD, PhD, senior investigator in the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint NIDA and NIAAA laboratory, said in a news release.

The study was published online in Molecular Psychiatry.
 

There is a “critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD,” the authors note, adding that neuroendocrine systems involved in alcohol craving and drinking “offer promising pharmacologic targets in this regard.”

“Both our team and others have observed that patients with AUD often present with changes in peripheral hormones, including aldosterone, which plays a key role in regulating blood pressure and electrolytes,” Dr. Leggio said in an interview.

Spironolactone is a nonselective mineralocorticoid receptor (MT) antagonist. In studies in animal models, investigators said they found “an inverse correlation between alcohol drinking and the expression of the MR in the amygdala, a key brain region in the development and maintenance of AUD and addiction in general.”

Taken together, this led them to hypothesize that blocking the MR, which is the mechanism of action of spironolactone, “could be a novel pharmacotherapeutic approach for AUD,” he said.

Previous research by the same group of researchers suggested spironolactone “may be a potential new medication to treat patients with AUD.” The present study expanded on those findings and consisted of a three-part investigation.

In the current study, the investigators tested different dosages of spironolactone on binge-like alcohol consumption in male and female mice and assessed food and water intake, blood alcohol levels, motor coordination, and spontaneous locomotion.

They then tested the effects of different dosages of spironolactone injections on operant alcohol self-administration in alcohol-dependent and nondependent male and female rats, also testing blood alcohol levels and motor coordination.

Finally, they analyzed health records of veterans to examine the association between at least 60 continuous days of spironolactone treatment and self-reported alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]).

Each of the spironolactone-exposed patients was matched using propensity scores with up to five unexposed patients who had reported alcohol consumption in the 2 years prior to the index date.

The final analysis included a matched cohort of 10,726 spironolactone-exposed individuals who were matched to 34,461 unexposed individuals.
 

New targets

Spironolactone reduced alcohol intake in mice drinking a sweetened alcohol solution; a 2-way ANOVA revealed a main effect of dose (F 4,52 = 9.09; P < .0001) and sex, with female mice drinking more alcohol, compared to male mice (F 1,13 = 6.05; P = .02).

Post hoc comparisons showed that spironolactone at doses of 50, 100, and 200 mg/kg significantly reduced alcohol intake (P values = .007, .002, and .0001, respectively).

In mice drinking an unsweetened alcohol solution, the 2-way repeated measures ANOVA similarly found a main effect of dose (F 4,52 = 5.77; P = .0006), but not of sex (F 1,13 = 1.41; P = .25).

Spironolactone had no effect on the mice’s intake of a sweet solution without alcohol and had no impact on the consumption of food and water or on locomotion and coordination.

In rats, a 2-way ANOVA revealed a significant spironolactone effect of dose (F 3,66 = 43.95; P < .001), with a post hoc test indicating that spironolactone at 25, 50, and 75 mg/kg reduced alcohol self-administration in alcohol-dependent and nondependent rats (all P values = .0001).

In humans, among the exposed individuals in the matched cohort, 25%, 57%, and 18% received daily doses of spironolactone of less than 25 mg/day, 25-49 mg/day, and 50 mg/day or higher, respectively, with a median follow-up time of 542 (interquartile range, 337-730) days.

The AUDIT-C scores decreased during the study period in both treatment groups, with a larger decrease in average AUDIT-C scores among the exposed vs. unexposed individuals.

“These are very exciting times because, thanks to the progress in the addiction biomedical research field, we are increasing our understanding of the mechanisms how some people develop AUD; hence we can use this knowledge to identify new targets.” The current study “is an example of these ongoing efforts,” said Dr. Leggio.

“It is important to note that [these results] are important but preliminary.” At this juncture, “it would be too premature to think about prescribing spironolactone to treat AUD,” he added.

 

Exciting findings

Commenting on the study, Joyce Besheer, PhD, professor, department of psychiatry and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, called the study an “elegant demonstration of translational science.”

“While clinical trials will be needed to determine whether this medication is effective at reducing drinking in patients with AUD, these findings are exciting as they suggest that spironolactone may be a promising compound and new treatment options for AUD are much needed,” said Dr. Besheer, who was not involved with the current study.

Dr. Leggio agreed. “We now need prospective, placebo-controlled studies to assess the potential safety and efficacy of spironolactone in people with AUD,” he said.

This work was supported by the National Institutes of Health and the NIAAA. Dr. Leggio, study coauthors, and Dr. Besheer declare no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Spironolactone, a potassium-sparing diuretic typically used to treat heart failure and hypertension, shows promise in treating alcohol use disorder (AUD), new research suggests.

Researchers at the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and Yale University, New Haven, Conn., investigated the impact of spironolactone on AUD.

Initially, they studied rodents and found that spironolactone reduced binge drinking in mice and reduced self-administration of alcohol in rats without adversely affecting food or water intake or causing motor or coordination problems.

They also analyzed electronic health records of patients drawn from the United States Veterans Affairs health care system to explore potential changes in alcohol use after spironolactone treatment was initiated for other conditions and found a significant link between spironolactone treatment and reduction in self-reported alcohol consumption, with the largest effects observed among those who reported hazardous/heavy episodic alcohol use prior to starting spironolactone treatment.

“Combining findings across three species and different types of research studies, and then seeing similarities in these data, gives us confidence that we are onto something potentially important scientifically and clinically,” senior coauthor Lorenzo Leggio, MD, PhD, senior investigator in the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint NIDA and NIAAA laboratory, said in a news release.

The study was published online in Molecular Psychiatry.
 

There is a “critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD,” the authors note, adding that neuroendocrine systems involved in alcohol craving and drinking “offer promising pharmacologic targets in this regard.”

“Both our team and others have observed that patients with AUD often present with changes in peripheral hormones, including aldosterone, which plays a key role in regulating blood pressure and electrolytes,” Dr. Leggio said in an interview.

Spironolactone is a nonselective mineralocorticoid receptor (MT) antagonist. In studies in animal models, investigators said they found “an inverse correlation between alcohol drinking and the expression of the MR in the amygdala, a key brain region in the development and maintenance of AUD and addiction in general.”

Taken together, this led them to hypothesize that blocking the MR, which is the mechanism of action of spironolactone, “could be a novel pharmacotherapeutic approach for AUD,” he said.

Previous research by the same group of researchers suggested spironolactone “may be a potential new medication to treat patients with AUD.” The present study expanded on those findings and consisted of a three-part investigation.

In the current study, the investigators tested different dosages of spironolactone on binge-like alcohol consumption in male and female mice and assessed food and water intake, blood alcohol levels, motor coordination, and spontaneous locomotion.

They then tested the effects of different dosages of spironolactone injections on operant alcohol self-administration in alcohol-dependent and nondependent male and female rats, also testing blood alcohol levels and motor coordination.

Finally, they analyzed health records of veterans to examine the association between at least 60 continuous days of spironolactone treatment and self-reported alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]).

Each of the spironolactone-exposed patients was matched using propensity scores with up to five unexposed patients who had reported alcohol consumption in the 2 years prior to the index date.

The final analysis included a matched cohort of 10,726 spironolactone-exposed individuals who were matched to 34,461 unexposed individuals.
 

New targets

Spironolactone reduced alcohol intake in mice drinking a sweetened alcohol solution; a 2-way ANOVA revealed a main effect of dose (F 4,52 = 9.09; P < .0001) and sex, with female mice drinking more alcohol, compared to male mice (F 1,13 = 6.05; P = .02).

Post hoc comparisons showed that spironolactone at doses of 50, 100, and 200 mg/kg significantly reduced alcohol intake (P values = .007, .002, and .0001, respectively).

In mice drinking an unsweetened alcohol solution, the 2-way repeated measures ANOVA similarly found a main effect of dose (F 4,52 = 5.77; P = .0006), but not of sex (F 1,13 = 1.41; P = .25).

Spironolactone had no effect on the mice’s intake of a sweet solution without alcohol and had no impact on the consumption of food and water or on locomotion and coordination.

In rats, a 2-way ANOVA revealed a significant spironolactone effect of dose (F 3,66 = 43.95; P < .001), with a post hoc test indicating that spironolactone at 25, 50, and 75 mg/kg reduced alcohol self-administration in alcohol-dependent and nondependent rats (all P values = .0001).

In humans, among the exposed individuals in the matched cohort, 25%, 57%, and 18% received daily doses of spironolactone of less than 25 mg/day, 25-49 mg/day, and 50 mg/day or higher, respectively, with a median follow-up time of 542 (interquartile range, 337-730) days.

The AUDIT-C scores decreased during the study period in both treatment groups, with a larger decrease in average AUDIT-C scores among the exposed vs. unexposed individuals.

“These are very exciting times because, thanks to the progress in the addiction biomedical research field, we are increasing our understanding of the mechanisms how some people develop AUD; hence we can use this knowledge to identify new targets.” The current study “is an example of these ongoing efforts,” said Dr. Leggio.

“It is important to note that [these results] are important but preliminary.” At this juncture, “it would be too premature to think about prescribing spironolactone to treat AUD,” he added.

 

Exciting findings

Commenting on the study, Joyce Besheer, PhD, professor, department of psychiatry and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, called the study an “elegant demonstration of translational science.”

“While clinical trials will be needed to determine whether this medication is effective at reducing drinking in patients with AUD, these findings are exciting as they suggest that spironolactone may be a promising compound and new treatment options for AUD are much needed,” said Dr. Besheer, who was not involved with the current study.

Dr. Leggio agreed. “We now need prospective, placebo-controlled studies to assess the potential safety and efficacy of spironolactone in people with AUD,” he said.

This work was supported by the National Institutes of Health and the NIAAA. Dr. Leggio, study coauthors, and Dr. Besheer declare no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Spironolactone, a potassium-sparing diuretic typically used to treat heart failure and hypertension, shows promise in treating alcohol use disorder (AUD), new research suggests.

Researchers at the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and Yale University, New Haven, Conn., investigated the impact of spironolactone on AUD.

Initially, they studied rodents and found that spironolactone reduced binge drinking in mice and reduced self-administration of alcohol in rats without adversely affecting food or water intake or causing motor or coordination problems.

They also analyzed electronic health records of patients drawn from the United States Veterans Affairs health care system to explore potential changes in alcohol use after spironolactone treatment was initiated for other conditions and found a significant link between spironolactone treatment and reduction in self-reported alcohol consumption, with the largest effects observed among those who reported hazardous/heavy episodic alcohol use prior to starting spironolactone treatment.

“Combining findings across three species and different types of research studies, and then seeing similarities in these data, gives us confidence that we are onto something potentially important scientifically and clinically,” senior coauthor Lorenzo Leggio, MD, PhD, senior investigator in the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint NIDA and NIAAA laboratory, said in a news release.

The study was published online in Molecular Psychiatry.
 

There is a “critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD,” the authors note, adding that neuroendocrine systems involved in alcohol craving and drinking “offer promising pharmacologic targets in this regard.”

“Both our team and others have observed that patients with AUD often present with changes in peripheral hormones, including aldosterone, which plays a key role in regulating blood pressure and electrolytes,” Dr. Leggio said in an interview.

Spironolactone is a nonselective mineralocorticoid receptor (MT) antagonist. In studies in animal models, investigators said they found “an inverse correlation between alcohol drinking and the expression of the MR in the amygdala, a key brain region in the development and maintenance of AUD and addiction in general.”

Taken together, this led them to hypothesize that blocking the MR, which is the mechanism of action of spironolactone, “could be a novel pharmacotherapeutic approach for AUD,” he said.

Previous research by the same group of researchers suggested spironolactone “may be a potential new medication to treat patients with AUD.” The present study expanded on those findings and consisted of a three-part investigation.

In the current study, the investigators tested different dosages of spironolactone on binge-like alcohol consumption in male and female mice and assessed food and water intake, blood alcohol levels, motor coordination, and spontaneous locomotion.

They then tested the effects of different dosages of spironolactone injections on operant alcohol self-administration in alcohol-dependent and nondependent male and female rats, also testing blood alcohol levels and motor coordination.

Finally, they analyzed health records of veterans to examine the association between at least 60 continuous days of spironolactone treatment and self-reported alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]).

Each of the spironolactone-exposed patients was matched using propensity scores with up to five unexposed patients who had reported alcohol consumption in the 2 years prior to the index date.

The final analysis included a matched cohort of 10,726 spironolactone-exposed individuals who were matched to 34,461 unexposed individuals.
 

New targets

Spironolactone reduced alcohol intake in mice drinking a sweetened alcohol solution; a 2-way ANOVA revealed a main effect of dose (F 4,52 = 9.09; P < .0001) and sex, with female mice drinking more alcohol, compared to male mice (F 1,13 = 6.05; P = .02).

Post hoc comparisons showed that spironolactone at doses of 50, 100, and 200 mg/kg significantly reduced alcohol intake (P values = .007, .002, and .0001, respectively).

In mice drinking an unsweetened alcohol solution, the 2-way repeated measures ANOVA similarly found a main effect of dose (F 4,52 = 5.77; P = .0006), but not of sex (F 1,13 = 1.41; P = .25).

Spironolactone had no effect on the mice’s intake of a sweet solution without alcohol and had no impact on the consumption of food and water or on locomotion and coordination.

In rats, a 2-way ANOVA revealed a significant spironolactone effect of dose (F 3,66 = 43.95; P < .001), with a post hoc test indicating that spironolactone at 25, 50, and 75 mg/kg reduced alcohol self-administration in alcohol-dependent and nondependent rats (all P values = .0001).

In humans, among the exposed individuals in the matched cohort, 25%, 57%, and 18% received daily doses of spironolactone of less than 25 mg/day, 25-49 mg/day, and 50 mg/day or higher, respectively, with a median follow-up time of 542 (interquartile range, 337-730) days.

The AUDIT-C scores decreased during the study period in both treatment groups, with a larger decrease in average AUDIT-C scores among the exposed vs. unexposed individuals.

“These are very exciting times because, thanks to the progress in the addiction biomedical research field, we are increasing our understanding of the mechanisms how some people develop AUD; hence we can use this knowledge to identify new targets.” The current study “is an example of these ongoing efforts,” said Dr. Leggio.

“It is important to note that [these results] are important but preliminary.” At this juncture, “it would be too premature to think about prescribing spironolactone to treat AUD,” he added.

 

Exciting findings

Commenting on the study, Joyce Besheer, PhD, professor, department of psychiatry and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, called the study an “elegant demonstration of translational science.”

“While clinical trials will be needed to determine whether this medication is effective at reducing drinking in patients with AUD, these findings are exciting as they suggest that spironolactone may be a promising compound and new treatment options for AUD are much needed,” said Dr. Besheer, who was not involved with the current study.

Dr. Leggio agreed. “We now need prospective, placebo-controlled studies to assess the potential safety and efficacy of spironolactone in people with AUD,” he said.

This work was supported by the National Institutes of Health and the NIAAA. Dr. Leggio, study coauthors, and Dr. Besheer declare no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Drinking two to three daily cups of – ground, instant, or decaffeinated – is associated with significant reductions in new cardiovascular disease (CVD) and mortality risk, compared with avoiding coffee, a new analysis of the prospective UK Biobank suggests.

Ground and instant coffee, but not decaffeinated coffee, also was associated with reduced risk of new-onset arrhythmia, including atrial fibrillation.

Visual_Intermezzo/iStock/Getty Images Plus

“Our study is the first to look at differences in coffee subtypes to tease out important differences which may explain some of the mechanisms through which coffee works,” Peter M. Kistler, MD, of the Alfred Hospital and Baker Heart and Diabetes Institute, Melbourne, Australia, told this news organization.

“Daily coffee intake should not be discouraged by physicians but rather considered part of a healthy diet,” Dr. Kistler said.

“This study supports that coffee is safe and even potentially beneficial, which is consistent with most of the prior evidence,” Carl “Chip” Lavie, MD, who wasn’t involved in the study, told this news organization.

“We do not prescribe coffee to patients, but for the majority who like coffee, they can be encouraged it is fine to take a few cups daily,” said Dr. Lavie, with the Ochsner Heart and Vascular Institute in New Orleans.

The study was published online in the European Journal of Preventive Cardiology.

 

Clear cardiovascular benefits

A total of 449,563 UK Biobank participants (median age 58 years; 55% women), who were free of arrhythmias or other CVD at baseline, reported in questionnaires their level of daily coffee intake and preferred type of coffee.

During more than 12.5 years of follow-up, 27,809 participants (6.2%) died.

Drinking one to five cups per day of ground or instant coffee (but not decaffeinated coffee) was associated with a significant reduction in incident arrhythmia. The lowest risk was with four to five cups per day for ground coffee (hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.76-0.91; P < .0001) and two to three cups per day for instant coffee (HR, 0.88; 95% CI, 0.85-0.92; P < .0001).

Habitual coffee drinking of up to five cups perday was also associated with significant reductions in the risk of incident CVD, when compared with nondrinkers.

Significant reductions in the risk of incident coronary heart disease (CHD) were associated with habitual coffee intake of up to five cups per day, with the lowest risk for CHD observed in those who consumed two to three cups per day (HR 0.89; 95% CI, 0.86-0.91; P < .0001).

Coffee consumption at all levels was linked to significant reduction in the risk of congestive cardiac failure (CCF) and ischemic stroke. The lowest risks were observed in those who consumed two to three cups per day, with HR, 0.83 (95% CI, 0.79-0.87; P < .0001) for CCF and HR, 0.84 (95% CI, 0.78-0.90; P < .0001) for ischemic stroke.

Death from any cause was significantly reduced for all coffee subtypes, with the greatest risk reduction seen with two to three cups per day for decaffeinated (HR, 0.86; 95% CI, 0.81-0.91; P < .0001); ground (HR, 0.73; 95% CI, 0.69-0.78; P < .0001); and instant coffee (HR, 0.89; 95% CI, 0.86-0.93; P < .0001).

“Coffee consumption is associated with cardiovascular benefits and should not empirically be discontinued in those with underlying heart rhythm disorders or cardiovascular disease,” Dr. Kistler told this news organization.

Plausible mechanisms

There are a number of proposed mechanisms to explain the benefits of coffee on CVD.

“Caffeine has antiarrhythmic properties through adenosine A1 and A2A receptor inhibition, hence the difference in effects of decaf vs. full-strength coffee on heart rhythm disorders,” Dr. Kistler explained.

Coffee has vasodilatory effects and coffee also contains antioxidant polyphenols, which reduce oxidative stress and modulate metabolism.

“The explanation for improved survival with habitual coffee consumption remains unclear,” Dr. Kistler said.

“Putative mechanisms include improved endothelial function, circulating antioxidants, improved insulin sensitivity, and reduced inflammation. Another potential mechanism includes the beneficial effects of coffee on metabolic syndrome,” he said.

“Caffeine has a role in weight loss through inhibition of gut fatty acid absorption and increase in basal metabolic rate. Furthermore, coffee has been associated with a significantly lower incidence of type 2 diabetes mellitus,” Dr. Kistler added.
 

Direction of relationship unclear

Charlotte Mills, PhD, University of Reading, England, said this study “adds to the body of evidence from observational trials associating moderate coffee consumption with cardioprotection, which looks promising.”

However, with the observational design, it’s unclear “which direction the relationship goes – for example, does coffee make you healthy or do inherently healthier people consume coffee? Randomized controlled trials are needed to fully understand the relationship between coffee and health before recommendations can be made,” Dr. Mills told the UK nonprofit Science Media Centre.

Annette Creedon, PhD, nutrition scientist with the British Nutrition Foundation, said it’s possible that respondents over- or underestimated the amount of coffee that they were consuming at the start of the study when they self-reported their intake.

“It is therefore difficult to determine whether the outcomes can be directly associated with the behaviors in coffee consumption reported at the start of the study,” she told the Science Media Centre.

The study had no funding. Dr. Kistler has received funding from Abbott Medical for consultancy and speaking engagements and fellowship support from Biosense Webster. Dr. Lavie has no relevant disclosures. Dr. Mills has worked in collaboration with Nestle on research relating to coffee and health funded by UKRI. Dr. Creedon has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Drinking two to three daily cups of – ground, instant, or decaffeinated – is associated with significant reductions in new cardiovascular disease (CVD) and mortality risk, compared with avoiding coffee, a new analysis of the prospective UK Biobank suggests.

Ground and instant coffee, but not decaffeinated coffee, also was associated with reduced risk of new-onset arrhythmia, including atrial fibrillation.

Visual_Intermezzo/iStock/Getty Images Plus

“Our study is the first to look at differences in coffee subtypes to tease out important differences which may explain some of the mechanisms through which coffee works,” Peter M. Kistler, MD, of the Alfred Hospital and Baker Heart and Diabetes Institute, Melbourne, Australia, told this news organization.

“Daily coffee intake should not be discouraged by physicians but rather considered part of a healthy diet,” Dr. Kistler said.

“This study supports that coffee is safe and even potentially beneficial, which is consistent with most of the prior evidence,” Carl “Chip” Lavie, MD, who wasn’t involved in the study, told this news organization.

“We do not prescribe coffee to patients, but for the majority who like coffee, they can be encouraged it is fine to take a few cups daily,” said Dr. Lavie, with the Ochsner Heart and Vascular Institute in New Orleans.

The study was published online in the European Journal of Preventive Cardiology.

 

Clear cardiovascular benefits

A total of 449,563 UK Biobank participants (median age 58 years; 55% women), who were free of arrhythmias or other CVD at baseline, reported in questionnaires their level of daily coffee intake and preferred type of coffee.

During more than 12.5 years of follow-up, 27,809 participants (6.2%) died.

Drinking one to five cups per day of ground or instant coffee (but not decaffeinated coffee) was associated with a significant reduction in incident arrhythmia. The lowest risk was with four to five cups per day for ground coffee (hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.76-0.91; P < .0001) and two to three cups per day for instant coffee (HR, 0.88; 95% CI, 0.85-0.92; P < .0001).

Habitual coffee drinking of up to five cups perday was also associated with significant reductions in the risk of incident CVD, when compared with nondrinkers.

Significant reductions in the risk of incident coronary heart disease (CHD) were associated with habitual coffee intake of up to five cups per day, with the lowest risk for CHD observed in those who consumed two to three cups per day (HR 0.89; 95% CI, 0.86-0.91; P < .0001).

Coffee consumption at all levels was linked to significant reduction in the risk of congestive cardiac failure (CCF) and ischemic stroke. The lowest risks were observed in those who consumed two to three cups per day, with HR, 0.83 (95% CI, 0.79-0.87; P < .0001) for CCF and HR, 0.84 (95% CI, 0.78-0.90; P < .0001) for ischemic stroke.

Death from any cause was significantly reduced for all coffee subtypes, with the greatest risk reduction seen with two to three cups per day for decaffeinated (HR, 0.86; 95% CI, 0.81-0.91; P < .0001); ground (HR, 0.73; 95% CI, 0.69-0.78; P < .0001); and instant coffee (HR, 0.89; 95% CI, 0.86-0.93; P < .0001).

“Coffee consumption is associated with cardiovascular benefits and should not empirically be discontinued in those with underlying heart rhythm disorders or cardiovascular disease,” Dr. Kistler told this news organization.

Plausible mechanisms

There are a number of proposed mechanisms to explain the benefits of coffee on CVD.

“Caffeine has antiarrhythmic properties through adenosine A1 and A2A receptor inhibition, hence the difference in effects of decaf vs. full-strength coffee on heart rhythm disorders,” Dr. Kistler explained.

Coffee has vasodilatory effects and coffee also contains antioxidant polyphenols, which reduce oxidative stress and modulate metabolism.

“The explanation for improved survival with habitual coffee consumption remains unclear,” Dr. Kistler said.

“Putative mechanisms include improved endothelial function, circulating antioxidants, improved insulin sensitivity, and reduced inflammation. Another potential mechanism includes the beneficial effects of coffee on metabolic syndrome,” he said.

“Caffeine has a role in weight loss through inhibition of gut fatty acid absorption and increase in basal metabolic rate. Furthermore, coffee has been associated with a significantly lower incidence of type 2 diabetes mellitus,” Dr. Kistler added.
 

Direction of relationship unclear

Charlotte Mills, PhD, University of Reading, England, said this study “adds to the body of evidence from observational trials associating moderate coffee consumption with cardioprotection, which looks promising.”

However, with the observational design, it’s unclear “which direction the relationship goes – for example, does coffee make you healthy or do inherently healthier people consume coffee? Randomized controlled trials are needed to fully understand the relationship between coffee and health before recommendations can be made,” Dr. Mills told the UK nonprofit Science Media Centre.

Annette Creedon, PhD, nutrition scientist with the British Nutrition Foundation, said it’s possible that respondents over- or underestimated the amount of coffee that they were consuming at the start of the study when they self-reported their intake.

“It is therefore difficult to determine whether the outcomes can be directly associated with the behaviors in coffee consumption reported at the start of the study,” she told the Science Media Centre.

The study had no funding. Dr. Kistler has received funding from Abbott Medical for consultancy and speaking engagements and fellowship support from Biosense Webster. Dr. Lavie has no relevant disclosures. Dr. Mills has worked in collaboration with Nestle on research relating to coffee and health funded by UKRI. Dr. Creedon has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Drinking two to three daily cups of – ground, instant, or decaffeinated – is associated with significant reductions in new cardiovascular disease (CVD) and mortality risk, compared with avoiding coffee, a new analysis of the prospective UK Biobank suggests.

Ground and instant coffee, but not decaffeinated coffee, also was associated with reduced risk of new-onset arrhythmia, including atrial fibrillation.

Visual_Intermezzo/iStock/Getty Images Plus

“Our study is the first to look at differences in coffee subtypes to tease out important differences which may explain some of the mechanisms through which coffee works,” Peter M. Kistler, MD, of the Alfred Hospital and Baker Heart and Diabetes Institute, Melbourne, Australia, told this news organization.

“Daily coffee intake should not be discouraged by physicians but rather considered part of a healthy diet,” Dr. Kistler said.

“This study supports that coffee is safe and even potentially beneficial, which is consistent with most of the prior evidence,” Carl “Chip” Lavie, MD, who wasn’t involved in the study, told this news organization.

“We do not prescribe coffee to patients, but for the majority who like coffee, they can be encouraged it is fine to take a few cups daily,” said Dr. Lavie, with the Ochsner Heart and Vascular Institute in New Orleans.

The study was published online in the European Journal of Preventive Cardiology.

 

Clear cardiovascular benefits

A total of 449,563 UK Biobank participants (median age 58 years; 55% women), who were free of arrhythmias or other CVD at baseline, reported in questionnaires their level of daily coffee intake and preferred type of coffee.

During more than 12.5 years of follow-up, 27,809 participants (6.2%) died.

Drinking one to five cups per day of ground or instant coffee (but not decaffeinated coffee) was associated with a significant reduction in incident arrhythmia. The lowest risk was with four to five cups per day for ground coffee (hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.76-0.91; P < .0001) and two to three cups per day for instant coffee (HR, 0.88; 95% CI, 0.85-0.92; P < .0001).

Habitual coffee drinking of up to five cups perday was also associated with significant reductions in the risk of incident CVD, when compared with nondrinkers.

Significant reductions in the risk of incident coronary heart disease (CHD) were associated with habitual coffee intake of up to five cups per day, with the lowest risk for CHD observed in those who consumed two to three cups per day (HR 0.89; 95% CI, 0.86-0.91; P < .0001).

Coffee consumption at all levels was linked to significant reduction in the risk of congestive cardiac failure (CCF) and ischemic stroke. The lowest risks were observed in those who consumed two to three cups per day, with HR, 0.83 (95% CI, 0.79-0.87; P < .0001) for CCF and HR, 0.84 (95% CI, 0.78-0.90; P < .0001) for ischemic stroke.

Death from any cause was significantly reduced for all coffee subtypes, with the greatest risk reduction seen with two to three cups per day for decaffeinated (HR, 0.86; 95% CI, 0.81-0.91; P < .0001); ground (HR, 0.73; 95% CI, 0.69-0.78; P < .0001); and instant coffee (HR, 0.89; 95% CI, 0.86-0.93; P < .0001).

“Coffee consumption is associated with cardiovascular benefits and should not empirically be discontinued in those with underlying heart rhythm disorders or cardiovascular disease,” Dr. Kistler told this news organization.

Plausible mechanisms

There are a number of proposed mechanisms to explain the benefits of coffee on CVD.

“Caffeine has antiarrhythmic properties through adenosine A1 and A2A receptor inhibition, hence the difference in effects of decaf vs. full-strength coffee on heart rhythm disorders,” Dr. Kistler explained.

Coffee has vasodilatory effects and coffee also contains antioxidant polyphenols, which reduce oxidative stress and modulate metabolism.

“The explanation for improved survival with habitual coffee consumption remains unclear,” Dr. Kistler said.

“Putative mechanisms include improved endothelial function, circulating antioxidants, improved insulin sensitivity, and reduced inflammation. Another potential mechanism includes the beneficial effects of coffee on metabolic syndrome,” he said.

“Caffeine has a role in weight loss through inhibition of gut fatty acid absorption and increase in basal metabolic rate. Furthermore, coffee has been associated with a significantly lower incidence of type 2 diabetes mellitus,” Dr. Kistler added.
 

Direction of relationship unclear

Charlotte Mills, PhD, University of Reading, England, said this study “adds to the body of evidence from observational trials associating moderate coffee consumption with cardioprotection, which looks promising.”

However, with the observational design, it’s unclear “which direction the relationship goes – for example, does coffee make you healthy or do inherently healthier people consume coffee? Randomized controlled trials are needed to fully understand the relationship between coffee and health before recommendations can be made,” Dr. Mills told the UK nonprofit Science Media Centre.

Annette Creedon, PhD, nutrition scientist with the British Nutrition Foundation, said it’s possible that respondents over- or underestimated the amount of coffee that they were consuming at the start of the study when they self-reported their intake.

“It is therefore difficult to determine whether the outcomes can be directly associated with the behaviors in coffee consumption reported at the start of the study,” she told the Science Media Centre.

The study had no funding. Dr. Kistler has received funding from Abbott Medical for consultancy and speaking engagements and fellowship support from Biosense Webster. Dr. Lavie has no relevant disclosures. Dr. Mills has worked in collaboration with Nestle on research relating to coffee and health funded by UKRI. Dr. Creedon has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.

Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.

Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.

Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.

Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.

Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.

Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.

Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.

Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.

Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.

Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.

Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.

Long COVID: The name says it all. It’s an illness that, for many people, has not yet stopped.

Eric Roach became ill with COVID-19 in November 2020, and he’s still sick. “I have brain fog, memory loss,” says the 67-year-old Navy veteran from Spearfish, S.D. “The fatigue has just been insane.” 

Long COVID, more formally known as post-acute sequelae of COVID (PASC), is the lay term to describe when people start to recover, or seem to recover, from a bout of COVID-19 but then continue to suffer from symptoms. For some, it’s gone on for 2 years or longer. While the governments of the United Statesand several other countries formally recognize the existence of long COVID, the National Institutes of Health (NIH) has yet to formally define it. There’s no approved treatment, and the causes are not understood.

Here’s what is known: Long COVID is a postviral condition affecting a large percentage of people who become infected with the coronavirus. It can be utterly debilitating or mildly annoying, and it is affecting enough people to cause concern for employers, health insurers, and governments.
 

First, the many symptoms

According to the Centers for Disease Control and Prvention, long COVID symptoms may include:

• Tiredness or fatigue that interferes with daily life.
• Symptoms that get worse after physical or mental effort.
• Fever.
• Difficulty breathing or shortness of breath.
• Cough.
• Chest pain.
• Heart palpitations.
• Difficulty thinking or concentrating (sometimes referred to as “brain fog”).
• Headache.
• Sleep problems.
• Dizziness when standing.
• Pins-and-needles feelings.
• Change in smell or taste.
• Depression or anxiety.
• Diarrhea.
• Stomach pain.
• Joint or muscle pain.
• Rash.
• Changes in menstrual cycles.

“People with post-COVID conditions may develop or continue to have symptoms that are hard to explain and manage,” the CDC says on its website. “Clinical evaluations and results of routine blood tests, chest x-rays, and electrocardiograms may be normal. The symptoms are similar to those reported by people with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) and other poorly understood chronic illnesses that may occur after other infections.” 

Doctors may not fully appreciate the subtle nature of some of the symptoms. 

“People with these unexplained symptoms may be misunderstood by their health care providers, which can result in a long time for them to get a diagnosis and receive appropriate care or treatment,” the CDC says.

Health professionals should recognize that long COVID can be disabling, the U.S. Department of Health and Human Services says. “Long COVID can substantially limit a major life activity,” HHS says in civil rights guidance. One possible example: “A person with long COVID who has lung damage that causes shortness of breath, fatigue, and related effects is substantially limited in respiratory function, among other major life activities,” the HHS notes.
 

How many people are affected?

This has been difficult to judge because not everyone who has had COVID-19 gets tested for it and there are no formal diagnostic criteria yet for long COVID. The CDC estimates that 19% of patients in the United States who have ever had COVID-19 have long COVID symptoms. 

Some estimates go higher. A University of Oxford study in September 2021 found more than a third of patients had symptoms of long COVID between 3 months and 6 months after a COVID-19 diagnosis. As many as 55% of COVID-19 patients in one Chinese study had one or more lingering symptoms 2 years later, Lixue Huang, MD, of the China-Japan Friendship Hospital in Beijing, and colleagues reported in the journal Lancet Respiratory Medicine in May.

According to the CDC, age is a factor. “Older adults are less likely to have long COVID than younger adults. Nearly three times as many adults ages 50-59 currently have long COVID than those age 80 and older,” the CDC says. Women and racial and ethnic minorities are more likely to be affected.

Many people are experiencing neurological effects, such as the so-called brain fog, according to Ziyad Al-Aly, MD, of Washington University and the VA St. Louis Health Care System, and colleagues, whose report was published in Nature Medicine in September. They estimated that 6.6 million Americans have brain impairments associated with COVID infection.

“Some of the neurologic disorders reported here are serious chronic conditions that will impact some people for a lifetime,” they wrote. “Given the colossal scale of the pandemic, and even though the absolute numbers reported in this work are small, these may translate into a large number of affected individuals around the world – and this will likely contribute to a rise in the burden of neurologic diseases.”
 

Causes

It’s not clear what the underlying causes are, but most research points to a combination of factors. Suspects include ongoing inflammation, tiny blood clots, and reactivation of latent viruses. In May, Brent Palmer, PhD, of the University of Colorado, Denver, and colleagues found people with long COVID had persistent activation of T-cells that were specific for SARS-CoV-2.

COVID-19 itself can damage organs, and long COVID might be caused by ongoing damage. In August, Alexandros Rovas, MD, of University Hospital Munster in Germany, and colleagues found patients with long COVID had evidence of damage to their capillaries. “Whether, to what extent, and when the observed damage might be reversible remains unclear,” they wrote in the journal Angiogenesis.

People with long COVID have immune responses to other viruses, such as Epstein-Barr – evidence that COVID-19 might reactivate latent viruses. “Our data suggest the involvement of persistent antigen, reactivation of latent herpesviruses, and chronic inflammation,” immunobiologist Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., and colleagues wrote in a study posted in August that had not yet been peer-reviewed for publication.

This might be causing an autoimmune response. “The infection may cause the immune system to start making autoantibodies that attack a person’s own organs and tissues,” the NIH says.

There could be other factors. A study by Harvard researchers found that people who felt stressed, depressed, or lonely before catching COVID-19 were more likely to develop long COVID afterward. “Distress was more strongly associated with developing long COVID than physical health risk factors such as obesity, asthma, and hypertension,” Siwen Wang, MD, a research fellow with Harvard University’s T.H. Chan School of Public Health, Boston, said in a statement.  Plus, nearly 44% of those in the study developed COVID-19 infections after having been assessed for stress, Dr. Wang and colleagues reported in the journal JAMA Psychiatry.
 

Vaccine protection 

There’s evidence that vaccination protects against long COVID, both by preventing infection in the first place, but also even for people who have breakthrough infections.

A meta-analysis covering studies involving 17 million people found evidence vaccination might reduce the severity of COVID-19 or might help the body clear any lingering virus after an infection.

“Overall, vaccination was associated with reduced risks or odds of long COVID, with preliminary evidence suggesting that two doses are more effective than one dose,” wrote Cesar Fernandez de las Penas, PhD, of King Juan Carlos University in Madrid, and colleagues. Their report is in The Lancet’s eClinicalMedicine.

A team in Milan found that unvaccinated people in their study were nearly three times as likely to have serious symptoms for longer than 4 weeks compared to vaccinated volunteers. According to their report in JAMA, Elena Azzolini, MD, PhD, assistant professor at Humanitas Research Hospital, and colleagues found two or three doses of vaccine reduced the risk of hospitalization from COVID to 16% or 17% compared to 42% for the unvaccinated.
 

Treatments

With no diagnostic criteria and no understanding of the causes, it’s hard for doctors to determine treatments.

Most experts dealing with long COVID, even those at the specialty centers that have been set up at hospitals and health systems in the United States, recommend that patients start with their primary care doctors before moving on to specialists.

“The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford, England, and colleagues wrote in the journal The BMJ in September. “Patients with long COVID greatly value input from their primary care clinician. Generalist clinicians can help patients considerably by hearing the patient’s story and validating their experience … (and) making the diagnosis of long COVID (which does not have to be by exclusion) and excluding alternative diagnoses.”

Evidence is building that long COVID closely resembles other postviral conditions – something that can provide clues for treatment. For example, several studies indicate that exercise doesn’t help most patients.

But there are approaches that can work. Treatments may include pulmonary rehabilitation; autonomic conditioning therapy, which includes breathing therapy; and cognitive rehabilitation to relieve brain fog. Doctors are also trying the antidepressant amitriptyline to help with sleep disturbances and headaches; the antiseizure medication gabapentin to help with pain, numbness, and other neurological symptoms; and drugs to relieve low blood pressure in patients experiencing postural orthostatic tachycardia syndrome (POTS).

The NIH is sponsoring studies that have recruited just over 8,200 adults. And more than two dozen researchers from Harvard; Stanford; the University of California, San Francisco; the J. Craig Venter Institute; Johns Hopkins University; the University of Pennsylvania; Mount Sinai Hospitals; Cardiff University; and Yale announced in September they were forming the Long COVID Research Initiative to speed up studies.

The group, with funding from private enterprise, plans to conduct tissue biopsy, imaging studies, and autopsies and will search for potential biomarkers in the blood of patients.

A version of this article first appeared on WebMD.com.

Long COVID: The name says it all. It’s an illness that, for many people, has not yet stopped.

Eric Roach became ill with COVID-19 in November 2020, and he’s still sick. “I have brain fog, memory loss,” says the 67-year-old Navy veteran from Spearfish, S.D. “The fatigue has just been insane.” 

Long COVID, more formally known as post-acute sequelae of COVID (PASC), is the lay term to describe when people start to recover, or seem to recover, from a bout of COVID-19 but then continue to suffer from symptoms. For some, it’s gone on for 2 years or longer. While the governments of the United Statesand several other countries formally recognize the existence of long COVID, the National Institutes of Health (NIH) has yet to formally define it. There’s no approved treatment, and the causes are not understood.

Here’s what is known: Long COVID is a postviral condition affecting a large percentage of people who become infected with the coronavirus. It can be utterly debilitating or mildly annoying, and it is affecting enough people to cause concern for employers, health insurers, and governments.
 

First, the many symptoms

According to the Centers for Disease Control and Prvention, long COVID symptoms may include:

• Tiredness or fatigue that interferes with daily life.
• Symptoms that get worse after physical or mental effort.
• Fever.
• Difficulty breathing or shortness of breath.
• Cough.
• Chest pain.
• Heart palpitations.
• Difficulty thinking or concentrating (sometimes referred to as “brain fog”).
• Headache.
• Sleep problems.
• Dizziness when standing.
• Pins-and-needles feelings.
• Change in smell or taste.
• Depression or anxiety.
• Diarrhea.
• Stomach pain.
• Joint or muscle pain.
• Rash.
• Changes in menstrual cycles.

“People with post-COVID conditions may develop or continue to have symptoms that are hard to explain and manage,” the CDC says on its website. “Clinical evaluations and results of routine blood tests, chest x-rays, and electrocardiograms may be normal. The symptoms are similar to those reported by people with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) and other poorly understood chronic illnesses that may occur after other infections.” 

Doctors may not fully appreciate the subtle nature of some of the symptoms. 

“People with these unexplained symptoms may be misunderstood by their health care providers, which can result in a long time for them to get a diagnosis and receive appropriate care or treatment,” the CDC says.

Health professionals should recognize that long COVID can be disabling, the U.S. Department of Health and Human Services says. “Long COVID can substantially limit a major life activity,” HHS says in civil rights guidance. One possible example: “A person with long COVID who has lung damage that causes shortness of breath, fatigue, and related effects is substantially limited in respiratory function, among other major life activities,” the HHS notes.
 

How many people are affected?

This has been difficult to judge because not everyone who has had COVID-19 gets tested for it and there are no formal diagnostic criteria yet for long COVID. The CDC estimates that 19% of patients in the United States who have ever had COVID-19 have long COVID symptoms. 

Some estimates go higher. A University of Oxford study in September 2021 found more than a third of patients had symptoms of long COVID between 3 months and 6 months after a COVID-19 diagnosis. As many as 55% of COVID-19 patients in one Chinese study had one or more lingering symptoms 2 years later, Lixue Huang, MD, of the China-Japan Friendship Hospital in Beijing, and colleagues reported in the journal Lancet Respiratory Medicine in May.

According to the CDC, age is a factor. “Older adults are less likely to have long COVID than younger adults. Nearly three times as many adults ages 50-59 currently have long COVID than those age 80 and older,” the CDC says. Women and racial and ethnic minorities are more likely to be affected.

Many people are experiencing neurological effects, such as the so-called brain fog, according to Ziyad Al-Aly, MD, of Washington University and the VA St. Louis Health Care System, and colleagues, whose report was published in Nature Medicine in September. They estimated that 6.6 million Americans have brain impairments associated with COVID infection.

“Some of the neurologic disorders reported here are serious chronic conditions that will impact some people for a lifetime,” they wrote. “Given the colossal scale of the pandemic, and even though the absolute numbers reported in this work are small, these may translate into a large number of affected individuals around the world – and this will likely contribute to a rise in the burden of neurologic diseases.”
 

Causes

It’s not clear what the underlying causes are, but most research points to a combination of factors. Suspects include ongoing inflammation, tiny blood clots, and reactivation of latent viruses. In May, Brent Palmer, PhD, of the University of Colorado, Denver, and colleagues found people with long COVID had persistent activation of T-cells that were specific for SARS-CoV-2.

COVID-19 itself can damage organs, and long COVID might be caused by ongoing damage. In August, Alexandros Rovas, MD, of University Hospital Munster in Germany, and colleagues found patients with long COVID had evidence of damage to their capillaries. “Whether, to what extent, and when the observed damage might be reversible remains unclear,” they wrote in the journal Angiogenesis.

People with long COVID have immune responses to other viruses, such as Epstein-Barr – evidence that COVID-19 might reactivate latent viruses. “Our data suggest the involvement of persistent antigen, reactivation of latent herpesviruses, and chronic inflammation,” immunobiologist Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., and colleagues wrote in a study posted in August that had not yet been peer-reviewed for publication.

This might be causing an autoimmune response. “The infection may cause the immune system to start making autoantibodies that attack a person’s own organs and tissues,” the NIH says.

There could be other factors. A study by Harvard researchers found that people who felt stressed, depressed, or lonely before catching COVID-19 were more likely to develop long COVID afterward. “Distress was more strongly associated with developing long COVID than physical health risk factors such as obesity, asthma, and hypertension,” Siwen Wang, MD, a research fellow with Harvard University’s T.H. Chan School of Public Health, Boston, said in a statement.  Plus, nearly 44% of those in the study developed COVID-19 infections after having been assessed for stress, Dr. Wang and colleagues reported in the journal JAMA Psychiatry.
 

Vaccine protection 

There’s evidence that vaccination protects against long COVID, both by preventing infection in the first place, but also even for people who have breakthrough infections.

A meta-analysis covering studies involving 17 million people found evidence vaccination might reduce the severity of COVID-19 or might help the body clear any lingering virus after an infection.

“Overall, vaccination was associated with reduced risks or odds of long COVID, with preliminary evidence suggesting that two doses are more effective than one dose,” wrote Cesar Fernandez de las Penas, PhD, of King Juan Carlos University in Madrid, and colleagues. Their report is in The Lancet’s eClinicalMedicine.

A team in Milan found that unvaccinated people in their study were nearly three times as likely to have serious symptoms for longer than 4 weeks compared to vaccinated volunteers. According to their report in JAMA, Elena Azzolini, MD, PhD, assistant professor at Humanitas Research Hospital, and colleagues found two or three doses of vaccine reduced the risk of hospitalization from COVID to 16% or 17% compared to 42% for the unvaccinated.
 

Treatments

With no diagnostic criteria and no understanding of the causes, it’s hard for doctors to determine treatments.

Most experts dealing with long COVID, even those at the specialty centers that have been set up at hospitals and health systems in the United States, recommend that patients start with their primary care doctors before moving on to specialists.

“The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford, England, and colleagues wrote in the journal The BMJ in September. “Patients with long COVID greatly value input from their primary care clinician. Generalist clinicians can help patients considerably by hearing the patient’s story and validating their experience … (and) making the diagnosis of long COVID (which does not have to be by exclusion) and excluding alternative diagnoses.”

Evidence is building that long COVID closely resembles other postviral conditions – something that can provide clues for treatment. For example, several studies indicate that exercise doesn’t help most patients.

But there are approaches that can work. Treatments may include pulmonary rehabilitation; autonomic conditioning therapy, which includes breathing therapy; and cognitive rehabilitation to relieve brain fog. Doctors are also trying the antidepressant amitriptyline to help with sleep disturbances and headaches; the antiseizure medication gabapentin to help with pain, numbness, and other neurological symptoms; and drugs to relieve low blood pressure in patients experiencing postural orthostatic tachycardia syndrome (POTS).

The NIH is sponsoring studies that have recruited just over 8,200 adults. And more than two dozen researchers from Harvard; Stanford; the University of California, San Francisco; the J. Craig Venter Institute; Johns Hopkins University; the University of Pennsylvania; Mount Sinai Hospitals; Cardiff University; and Yale announced in September they were forming the Long COVID Research Initiative to speed up studies.

The group, with funding from private enterprise, plans to conduct tissue biopsy, imaging studies, and autopsies and will search for potential biomarkers in the blood of patients.

A version of this article first appeared on WebMD.com.

Long COVID: The name says it all. It’s an illness that, for many people, has not yet stopped.

Eric Roach became ill with COVID-19 in November 2020, and he’s still sick. “I have brain fog, memory loss,” says the 67-year-old Navy veteran from Spearfish, S.D. “The fatigue has just been insane.” 

Long COVID, more formally known as post-acute sequelae of COVID (PASC), is the lay term to describe when people start to recover, or seem to recover, from a bout of COVID-19 but then continue to suffer from symptoms. For some, it’s gone on for 2 years or longer. While the governments of the United Statesand several other countries formally recognize the existence of long COVID, the National Institutes of Health (NIH) has yet to formally define it. There’s no approved treatment, and the causes are not understood.

Here’s what is known: Long COVID is a postviral condition affecting a large percentage of people who become infected with the coronavirus. It can be utterly debilitating or mildly annoying, and it is affecting enough people to cause concern for employers, health insurers, and governments.
 

First, the many symptoms

According to the Centers for Disease Control and Prvention, long COVID symptoms may include:

• Tiredness or fatigue that interferes with daily life.
• Symptoms that get worse after physical or mental effort.
• Fever.
• Difficulty breathing or shortness of breath.
• Cough.
• Chest pain.
• Heart palpitations.
• Difficulty thinking or concentrating (sometimes referred to as “brain fog”).
• Headache.
• Sleep problems.
• Dizziness when standing.
• Pins-and-needles feelings.
• Change in smell or taste.
• Depression or anxiety.
• Diarrhea.
• Stomach pain.
• Joint or muscle pain.
• Rash.
• Changes in menstrual cycles.

“People with post-COVID conditions may develop or continue to have symptoms that are hard to explain and manage,” the CDC says on its website. “Clinical evaluations and results of routine blood tests, chest x-rays, and electrocardiograms may be normal. The symptoms are similar to those reported by people with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) and other poorly understood chronic illnesses that may occur after other infections.” 

Doctors may not fully appreciate the subtle nature of some of the symptoms. 

“People with these unexplained symptoms may be misunderstood by their health care providers, which can result in a long time for them to get a diagnosis and receive appropriate care or treatment,” the CDC says.

Health professionals should recognize that long COVID can be disabling, the U.S. Department of Health and Human Services says. “Long COVID can substantially limit a major life activity,” HHS says in civil rights guidance. One possible example: “A person with long COVID who has lung damage that causes shortness of breath, fatigue, and related effects is substantially limited in respiratory function, among other major life activities,” the HHS notes.
 

How many people are affected?

This has been difficult to judge because not everyone who has had COVID-19 gets tested for it and there are no formal diagnostic criteria yet for long COVID. The CDC estimates that 19% of patients in the United States who have ever had COVID-19 have long COVID symptoms. 

Some estimates go higher. A University of Oxford study in September 2021 found more than a third of patients had symptoms of long COVID between 3 months and 6 months after a COVID-19 diagnosis. As many as 55% of COVID-19 patients in one Chinese study had one or more lingering symptoms 2 years later, Lixue Huang, MD, of the China-Japan Friendship Hospital in Beijing, and colleagues reported in the journal Lancet Respiratory Medicine in May.

According to the CDC, age is a factor. “Older adults are less likely to have long COVID than younger adults. Nearly three times as many adults ages 50-59 currently have long COVID than those age 80 and older,” the CDC says. Women and racial and ethnic minorities are more likely to be affected.

Many people are experiencing neurological effects, such as the so-called brain fog, according to Ziyad Al-Aly, MD, of Washington University and the VA St. Louis Health Care System, and colleagues, whose report was published in Nature Medicine in September. They estimated that 6.6 million Americans have brain impairments associated with COVID infection.

“Some of the neurologic disorders reported here are serious chronic conditions that will impact some people for a lifetime,” they wrote. “Given the colossal scale of the pandemic, and even though the absolute numbers reported in this work are small, these may translate into a large number of affected individuals around the world – and this will likely contribute to a rise in the burden of neurologic diseases.”
 

Causes

It’s not clear what the underlying causes are, but most research points to a combination of factors. Suspects include ongoing inflammation, tiny blood clots, and reactivation of latent viruses. In May, Brent Palmer, PhD, of the University of Colorado, Denver, and colleagues found people with long COVID had persistent activation of T-cells that were specific for SARS-CoV-2.

COVID-19 itself can damage organs, and long COVID might be caused by ongoing damage. In August, Alexandros Rovas, MD, of University Hospital Munster in Germany, and colleagues found patients with long COVID had evidence of damage to their capillaries. “Whether, to what extent, and when the observed damage might be reversible remains unclear,” they wrote in the journal Angiogenesis.

People with long COVID have immune responses to other viruses, such as Epstein-Barr – evidence that COVID-19 might reactivate latent viruses. “Our data suggest the involvement of persistent antigen, reactivation of latent herpesviruses, and chronic inflammation,” immunobiologist Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., and colleagues wrote in a study posted in August that had not yet been peer-reviewed for publication.

This might be causing an autoimmune response. “The infection may cause the immune system to start making autoantibodies that attack a person’s own organs and tissues,” the NIH says.

There could be other factors. A study by Harvard researchers found that people who felt stressed, depressed, or lonely before catching COVID-19 were more likely to develop long COVID afterward. “Distress was more strongly associated with developing long COVID than physical health risk factors such as obesity, asthma, and hypertension,” Siwen Wang, MD, a research fellow with Harvard University’s T.H. Chan School of Public Health, Boston, said in a statement.  Plus, nearly 44% of those in the study developed COVID-19 infections after having been assessed for stress, Dr. Wang and colleagues reported in the journal JAMA Psychiatry.
 

Vaccine protection 

There’s evidence that vaccination protects against long COVID, both by preventing infection in the first place, but also even for people who have breakthrough infections.

A meta-analysis covering studies involving 17 million people found evidence vaccination might reduce the severity of COVID-19 or might help the body clear any lingering virus after an infection.

“Overall, vaccination was associated with reduced risks or odds of long COVID, with preliminary evidence suggesting that two doses are more effective than one dose,” wrote Cesar Fernandez de las Penas, PhD, of King Juan Carlos University in Madrid, and colleagues. Their report is in The Lancet’s eClinicalMedicine.

A team in Milan found that unvaccinated people in their study were nearly three times as likely to have serious symptoms for longer than 4 weeks compared to vaccinated volunteers. According to their report in JAMA, Elena Azzolini, MD, PhD, assistant professor at Humanitas Research Hospital, and colleagues found two or three doses of vaccine reduced the risk of hospitalization from COVID to 16% or 17% compared to 42% for the unvaccinated.
 

Treatments

With no diagnostic criteria and no understanding of the causes, it’s hard for doctors to determine treatments.

Most experts dealing with long COVID, even those at the specialty centers that have been set up at hospitals and health systems in the United States, recommend that patients start with their primary care doctors before moving on to specialists.

“The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford, England, and colleagues wrote in the journal The BMJ in September. “Patients with long COVID greatly value input from their primary care clinician. Generalist clinicians can help patients considerably by hearing the patient’s story and validating their experience … (and) making the diagnosis of long COVID (which does not have to be by exclusion) and excluding alternative diagnoses.”

Evidence is building that long COVID closely resembles other postviral conditions – something that can provide clues for treatment. For example, several studies indicate that exercise doesn’t help most patients.

But there are approaches that can work. Treatments may include pulmonary rehabilitation; autonomic conditioning therapy, which includes breathing therapy; and cognitive rehabilitation to relieve brain fog. Doctors are also trying the antidepressant amitriptyline to help with sleep disturbances and headaches; the antiseizure medication gabapentin to help with pain, numbness, and other neurological symptoms; and drugs to relieve low blood pressure in patients experiencing postural orthostatic tachycardia syndrome (POTS).

The NIH is sponsoring studies that have recruited just over 8,200 adults. And more than two dozen researchers from Harvard; Stanford; the University of California, San Francisco; the J. Craig Venter Institute; Johns Hopkins University; the University of Pennsylvania; Mount Sinai Hospitals; Cardiff University; and Yale announced in September they were forming the Long COVID Research Initiative to speed up studies.

The group, with funding from private enterprise, plans to conduct tissue biopsy, imaging studies, and autopsies and will search for potential biomarkers in the blood of patients.

A version of this article first appeared on WebMD.com.

Apremilast may have an overall benefit for patients with cardiometabolic disease and psoriasis, new results from a nonrandomized clinical trial suggest.

The trial, led by Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology and vice chair of clinical research in dermatology at the University of Pennsylvania, Philadelphia, found that apremilast (Otezla) has a neutral effect on aortic vascular inflammation in patients with moderate to severe psoriasis.

It also had variable, but generally favorable, associations with 68 cardiometabolic biomarkers tested and associations with reductions in both visceral and subcutaneous fat. Findings of the study were published online in JAMA Dermatology.

Fat reductions maintained at 1-year mark

The researchers found a 5%-6% reduction in subcutaneous and visceral fat at week 16 of the study that was maintained at the 1-year mark. “The fact that it was rock stable a year later is pretty encouraging,” Dr. Gelfand told this news organization.

Courtesy Dr. Joel M. Gelfand

As for effects on vascular inflammation, Dr. Gelfand said, “The good news is we didn’t find any adverse effects on aortic vascular inflammation, but we didn’t find any beneficial effects either. That was a little disappointing.

“The most surprising thing was really the effects on visceral adiposity,” he added. “I’m not aware of any other drug having demonstrated that effect.”

Michael S. Garshick, MD, a cardiologist with NYU Langone Health in New York, who was not involved with the trial, told this news organization that despite seemingly good epidemiologic evidence in observational studies that by treating psoriasis surrogates of cardiovascular risk can be reduced, this trial, like others before it, failed to reduce aortic vascular inflammation.

Courtesy NYU Langone

Seventy patients enrolled

In total, 70 patients with moderate to severe psoriasis were enrolled, 60 completed week 16, and 39 completed week 52 of the single-arm, open-label trial conducted between April 2017 and August 2021 at seven dermatology sites in the United States.

Participants took 30 mg of apremilast, an oral phosphodiesterase-4 (PDE-4) inhibitor approved for treating psoriasis and psoriatic arthritis, twice daily. Participants’ average age was 47.5 years; most were male (77.1%) and White (82.9%); almost 6% were Black. Average body mass index was 30 kg/m². Patients could not have received biologics within 90 days of study baseline (or 180 days for ustekinumab [Stelara]).

There was no change in aortic vascular inflammation at week 16 (target to background ratio, −0.02; 95% confidence interval [CI], −0.08 to 0.05; P = .61) or week 52 (target to background ratio, −0.07; 95% CI, −0.15 to 0.01; P = .09) compared with baseline.

“At week 16, there were reductions in levels of interleukin-1b, fetuin A, valine, leucine, and isoleucine,” the authors wrote, adding that at week 52, compared with baseline, “there were reductions in levels of ferritin, cholesterol efflux capacity, beta-hydroxybutyrate, acetone, and ketone bodies, and an increase in levels of apolipoprotein A-1.”

This study highlights the importance of screening, Dr. Garshick said.

He and Dr. Gelfand said people with psoriatic disease tend to be vastly underscreened for cardiovascular risk factors.

Dr. Gelfand said, “If we did what we knew worked – meaning we screened them for diabetes, we screen their cholesterol, we check their blood pressure, and we adequately treated those traditional cardiovascular risk factors, we probably could narrow the gap quite a bit” in terms of the lower life expectancy people face when they have more significant psoriasis.

Celgene was the initial funding sponsor; sponsorship was then transferred to Amgen. The authors designed, executed, analyzed, and reported the study. Celgene provided nonbinding input into study design, and Amgen provided nonbinding input into the reporting of results. Dr. Gelfand reported numerous disclosures with various pharmaceutical companies and organizations. Dr. Garshick reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Apremilast may have an overall benefit for patients with cardiometabolic disease and psoriasis, new results from a nonrandomized clinical trial suggest.

The trial, led by Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology and vice chair of clinical research in dermatology at the University of Pennsylvania, Philadelphia, found that apremilast (Otezla) has a neutral effect on aortic vascular inflammation in patients with moderate to severe psoriasis.

It also had variable, but generally favorable, associations with 68 cardiometabolic biomarkers tested and associations with reductions in both visceral and subcutaneous fat. Findings of the study were published online in JAMA Dermatology.

Fat reductions maintained at 1-year mark

The researchers found a 5%-6% reduction in subcutaneous and visceral fat at week 16 of the study that was maintained at the 1-year mark. “The fact that it was rock stable a year later is pretty encouraging,” Dr. Gelfand told this news organization.

Courtesy Dr. Joel M. Gelfand

As for effects on vascular inflammation, Dr. Gelfand said, “The good news is we didn’t find any adverse effects on aortic vascular inflammation, but we didn’t find any beneficial effects either. That was a little disappointing.

“The most surprising thing was really the effects on visceral adiposity,” he added. “I’m not aware of any other drug having demonstrated that effect.”

Michael S. Garshick, MD, a cardiologist with NYU Langone Health in New York, who was not involved with the trial, told this news organization that despite seemingly good epidemiologic evidence in observational studies that by treating psoriasis surrogates of cardiovascular risk can be reduced, this trial, like others before it, failed to reduce aortic vascular inflammation.

Courtesy NYU Langone

Seventy patients enrolled

In total, 70 patients with moderate to severe psoriasis were enrolled, 60 completed week 16, and 39 completed week 52 of the single-arm, open-label trial conducted between April 2017 and August 2021 at seven dermatology sites in the United States.

Participants took 30 mg of apremilast, an oral phosphodiesterase-4 (PDE-4) inhibitor approved for treating psoriasis and psoriatic arthritis, twice daily. Participants’ average age was 47.5 years; most were male (77.1%) and White (82.9%); almost 6% were Black. Average body mass index was 30 kg/m². Patients could not have received biologics within 90 days of study baseline (or 180 days for ustekinumab [Stelara]).

There was no change in aortic vascular inflammation at week 16 (target to background ratio, −0.02; 95% confidence interval [CI], −0.08 to 0.05; P = .61) or week 52 (target to background ratio, −0.07; 95% CI, −0.15 to 0.01; P = .09) compared with baseline.

“At week 16, there were reductions in levels of interleukin-1b, fetuin A, valine, leucine, and isoleucine,” the authors wrote, adding that at week 52, compared with baseline, “there were reductions in levels of ferritin, cholesterol efflux capacity, beta-hydroxybutyrate, acetone, and ketone bodies, and an increase in levels of apolipoprotein A-1.”

This study highlights the importance of screening, Dr. Garshick said.

He and Dr. Gelfand said people with psoriatic disease tend to be vastly underscreened for cardiovascular risk factors.

Dr. Gelfand said, “If we did what we knew worked – meaning we screened them for diabetes, we screen their cholesterol, we check their blood pressure, and we adequately treated those traditional cardiovascular risk factors, we probably could narrow the gap quite a bit” in terms of the lower life expectancy people face when they have more significant psoriasis.

Celgene was the initial funding sponsor; sponsorship was then transferred to Amgen. The authors designed, executed, analyzed, and reported the study. Celgene provided nonbinding input into study design, and Amgen provided nonbinding input into the reporting of results. Dr. Gelfand reported numerous disclosures with various pharmaceutical companies and organizations. Dr. Garshick reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Apremilast may have an overall benefit for patients with cardiometabolic disease and psoriasis, new results from a nonrandomized clinical trial suggest.

The trial, led by Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology and vice chair of clinical research in dermatology at the University of Pennsylvania, Philadelphia, found that apremilast (Otezla) has a neutral effect on aortic vascular inflammation in patients with moderate to severe psoriasis.

It also had variable, but generally favorable, associations with 68 cardiometabolic biomarkers tested and associations with reductions in both visceral and subcutaneous fat. Findings of the study were published online in JAMA Dermatology.

Fat reductions maintained at 1-year mark

The researchers found a 5%-6% reduction in subcutaneous and visceral fat at week 16 of the study that was maintained at the 1-year mark. “The fact that it was rock stable a year later is pretty encouraging,” Dr. Gelfand told this news organization.

Courtesy Dr. Joel M. Gelfand

As for effects on vascular inflammation, Dr. Gelfand said, “The good news is we didn’t find any adverse effects on aortic vascular inflammation, but we didn’t find any beneficial effects either. That was a little disappointing.

“The most surprising thing was really the effects on visceral adiposity,” he added. “I’m not aware of any other drug having demonstrated that effect.”

Michael S. Garshick, MD, a cardiologist with NYU Langone Health in New York, who was not involved with the trial, told this news organization that despite seemingly good epidemiologic evidence in observational studies that by treating psoriasis surrogates of cardiovascular risk can be reduced, this trial, like others before it, failed to reduce aortic vascular inflammation.

Courtesy NYU Langone

Seventy patients enrolled

In total, 70 patients with moderate to severe psoriasis were enrolled, 60 completed week 16, and 39 completed week 52 of the single-arm, open-label trial conducted between April 2017 and August 2021 at seven dermatology sites in the United States.

Participants took 30 mg of apremilast, an oral phosphodiesterase-4 (PDE-4) inhibitor approved for treating psoriasis and psoriatic arthritis, twice daily. Participants’ average age was 47.5 years; most were male (77.1%) and White (82.9%); almost 6% were Black. Average body mass index was 30 kg/m². Patients could not have received biologics within 90 days of study baseline (or 180 days for ustekinumab [Stelara]).

There was no change in aortic vascular inflammation at week 16 (target to background ratio, −0.02; 95% confidence interval [CI], −0.08 to 0.05; P = .61) or week 52 (target to background ratio, −0.07; 95% CI, −0.15 to 0.01; P = .09) compared with baseline.

“At week 16, there were reductions in levels of interleukin-1b, fetuin A, valine, leucine, and isoleucine,” the authors wrote, adding that at week 52, compared with baseline, “there were reductions in levels of ferritin, cholesterol efflux capacity, beta-hydroxybutyrate, acetone, and ketone bodies, and an increase in levels of apolipoprotein A-1.”

This study highlights the importance of screening, Dr. Garshick said.

He and Dr. Gelfand said people with psoriatic disease tend to be vastly underscreened for cardiovascular risk factors.

Dr. Gelfand said, “If we did what we knew worked – meaning we screened them for diabetes, we screen their cholesterol, we check their blood pressure, and we adequately treated those traditional cardiovascular risk factors, we probably could narrow the gap quite a bit” in terms of the lower life expectancy people face when they have more significant psoriasis.

Celgene was the initial funding sponsor; sponsorship was then transferred to Amgen. The authors designed, executed, analyzed, and reported the study. Celgene provided nonbinding input into study design, and Amgen provided nonbinding input into the reporting of results. Dr. Gelfand reported numerous disclosures with various pharmaceutical companies and organizations. Dr. Garshick reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

STOCKHOLM – Weight loss should be a co–primary management goal for type 2 diabetes in adults, according to a new comprehensive joint consensus report from the European Association for the Study of Diabetes and the American Diabetes Association.

And while metformin is still recommended as first-line therapy for patients with type 2 diabetes with no other comorbidities, the statement expands the indications for use of other agents or combinations of agents as initial therapy for subgroups of patients, as part of individualized and patient-centered decision-making.

Last updated in 2019, the new “Management of Hyperglycemia in Type 2 Diabetes” statement also places increased emphasis on social determinants of health, incorporates recent clinical trial data for cardiovascular and kidney outcomes for sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagonlike peptide–1 (GLP-1) agonists to broaden recommendations for cardiorenal protection, and discusses health behaviors such as sleep and sitting. It also targets a wider audience than in the past by addressing health system organization to optimize delivery of diabetes care.

The new statement was presented during a 90-minute session at the annual meeting of the EASD, with 12 of its 14 European and American authors as presenters. The document was simultaneously published in Diabetologia and Diabetes Care.

During the discussion, panel member Jennifer Brigitte Green, MD, commented: “Many of these recommendations are not new. They’re modest revisions of recommendations that have been in place for years, but we know that actual implementation rates of use of these drugs in patients with established comorbidities are very low.”

“I think it’s time for communities, health care systems, etc, to actually introduce these as expectations of care... to assess quality because unless it’s considered formally to be a requirement of care I just don’t think we’re going to move that needle very much,” added Dr. Green, who is professor of medicine at Duke University, Durham, N.C.

Vanita R. Aroda, MD, of the division of endocrinology, diabetes, and hypertension at Brigham and Women’s Hospital, Boston, commented: “In the past, sometimes these recommendations created fodder for debate, but I don’t think this one will. It’s just really solidly evidence based, with the rationales presented throughout, including the figures. I think just having very clear evidence-based directions should support their dissemination and use.”
 

Weight management plays a prominent role in treatment

In an interview, writing panel cochair John B. Buse, MD, PhD, said: “We are saying that the four major components of type 2 diabetes care are glycemic management, cardiovascular risk management, weight management, and prevention of end-organ damage, particularly with regard to cardiorenal risk.”

“The weight management piece is much more explicit now,” said Dr. Buse, director of the Diabetes Center at the University of North Carolina at Chapel Hill.

He noted that recent evidence from the intensive lifestyle trial DiRECT, conducted in the United Kingdom, the bariatric surgery literature, and the emergence of potent weight-loss drugs have meant that “achieving 10%-15% body weight loss is now possible.

“So, aiming for remission is something that might be attractive to patients and providers. This could be based on weight management, with the [chosen] method based on shared decision-making.”

According to the new report: “Weight loss of 5%-10% confers metabolic improvement; weight loss of 10%-15% or more can have a disease-modifying effect and lead to remission of diabetes, defined as normal blood glucose levels for 3 months or more in the absence of pharmacological therapy in a 2021 consensus report.”

“Weight loss may exert benefits that extend beyond glycemic management to improve risk factors for cardiometabolic disease and quality of life,” it adds.
 

Individualization featured throughout

The report’s sections cover principles of care, including the importance of diabetes self-management education and support and avoidance of therapeutic inertia. Detailed guidance addresses therapeutic options including lifestyle, weight management, and pharmacotherapy for treating type 2 diabetes.

Another entire section is devoted to personalizing treatment approaches based on individual characteristics, including new evidence from cardiorenal outcomes studies for SGLT2 inhibitors and GLP-1 agonists that have come out since the last consensus report.

The document advises: “Consider initial combination therapy with glucose-lowering agents, especially in those with high [hemoglobin] A1c at diagnosis (that is, > 70 mmol/mol [> 8.5%]), in younger people with type 2 diabetes (regardless of A1c), and in those in whom a stepwise approach would delay access to agents that provide cardiorenal protection beyond their glucose-lowering effects.”
 

Designed to be used and user-friendly

Under the “Putting it all together: strategies for implementation” section, several lists of “practical tips for clinicians” are provided for many of the topics covered.

A series of colorful infographics are included as well, addressing the “decision cycle for person-centered glycemic management in type 2 diabetes,” including a chart summarizing characteristics of available glucose-lowering medications, including cardiorenal protection.

Also mentioned is the importance of 24-hour physical behaviors (including sleep, sitting, and sweating) and the impact on cardiometabolic health, use of a “holistic person-centered approach” to type 2 diabetes management, and an algorithm on insulin use.

Dr. Buse has financial ties to numerous drug and device companies. Dr. Green is a consultant for AstraZeneca, Pfizer, Boehringer Ingelheim/Lilly, Bayer, Sanofi, Anji, Vertex/ICON, and Valo. Dr. Aroda has served as a consultant for Applied Therapeutics, Duke, Fractyl, Novo Nordisk, Pfizer, and Sanofi.

A version of this article first appeared on Medscape.com.